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New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Niko said:
Either 2 reporters got it wrong or there is a piece missing from the public domain.


AND this one:
Click to expand...
Actually, in one sense all are right. The Vietnam case the WHO mentioned in their update actually had both changes, H274Y and N294S. The patient was the 14F infected by her brother (who also infected his nurse and the grandfather had H5N1 antibodies). No one on that cluster died, although the index case was hospitalized for something like 85 days.

The case was written up in Nature in December 2005. Two sequences were deposited. One was wild type at both positions and the other had an ambiguous change (represent wild type and H274Y).

The amount of resistance for N294S was about 10X (10X as much Tamiflu was require when treating H294S compared to wild type to get the same inhibition (IC50).

Comparing that case of N294S to Egypt is apples and oranges. The Egyptian cases both had N294S without a hint of H274Y or wild type N at 294.

N294S was not due to tamiflu treatment of those two patients.
 
Last edited:
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

niman said:
Commentary at

http://www.recombinomics.com/News/01190701/H5N1_Egypt_N294S_Transmission.html
Click to expand...

Commentary

Transmission of N294S Tamiflu Resistance In Egypt
Recombinomics Commentary
January 19, 2007

Current laboratory testing suggests that the level of reduced susceptibility is moderate. This mutation has previously been identified in Viet Nam in one case in 2005

The above comments from the WHO update on the N294S Tamiflu resistance markers in the Gharbiya cluster, describe a patient (14F) in Hanoi in 2005, who developed Tamiflu resistance via two markers, H274Y and N294S. H274Y was present at higher levels and was associated with a high level of Tamiflu inhibition in vitro, indicating the clinical role of N294S in that patient was minimal. The above case further suggests that the two patients in the Gharbiya cluster were infected with H5N1 that had already acquired N294S.

The evidence for N294S prior to Tamiflu use is significant. The NA sequences generated by US NAMRU-3 were from direct sequencing of samples collected two days after the start of Tamiflu treatment (2 X 75 mg). The two sequences had no evidence of the wild type N at position 294 or the common change associated with Tamiflu resistance in H5N1 infected patients, H274Y. Since all four cluster members developed symptoms prior to Tamiflu treatment of any cluster member, the N294S would have had to have arisen independently in each patient. Moreover, N294S has been found in H5N1 infected ducks in China (Zhejiang and Hong Kong).

Therefore, the likelihood that N294S independently arose in both patients in response to Tamiflu treatment remains low.

Further testing of H5N1 patients and birds in Egypt will provide information of the frequency of N294S in Qinghai H5N1 in the region.

.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

per WHO release above...
....Current laboratory testing suggests that the level of reduced susceptibility is moderate....
Click to expand...

per Niman post above.....
The amount of resistance for N294S was about 10X (10X as much Tamiflu was require when treating H294S compared to wild type to get the same inhibition (IC50).
Click to expand...

How can requiring 10X as much tamiflu be considered moderate resistance?

.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

AlaskaDenise said:
per WHO release above...


per Niman post above.....


How can requiring 10X as much tamiflu be considered moderate resistance?

.
Click to expand...

N294S has a weaker effect than H274Y, which is considered strong, but Tamiflu is already teetering, and N294S pushes it off the cliff (although Roche launched its damage control program today).
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

All this highlight the need to quickly explore others avenue in the antiviral field.

Instead of stockpilling an expensive patented organic chemistry molecule that exhibit some sign of neurotoxicity;
http://www.fda.gov/medwatch/safety/2006/safety06.htm#tamiflu
Instead of stockpilling only one expensive antiviral when more and more proof of resistance developement is seen...

<!--[if !supportLists]-->-.<!--[endif]-->Baz, M., Abed, Y.,McDonald, J., Boivin, G., Characterization of Multidrug-Resistant Influenza A/H3N2 Viruses Shed during 1 Year by an Immunocompromised Child., Clin Infect Dis. 2006 Dec 15;43(12):1555-1561. 2006.<o:p></o:p>
<!--[if !supportLists]-->-.<!--[endif]-->de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC, et al. Oseltamivir resistance during treatment of influenza A (H5N1) infection. N Engl J Med.;353:2667?72, 2005<o:p></o:p>
<!--[if !supportLists]--><!--[endif]-->-.T.Suzuki, Y. Suzuki, and Y. Kawaoka. Avian flu : Isolation of drug-resistant H5N1 virus. Science 437 :1108, 2005<o:p></o:p>
<!--[if !supportLists]-->-.<!--[endif]-->Baz, M., Abed, Y.,McDonald, J., Boivin, G., Characterization of Multidrug-Resistant Influenza A/H3N2 Viruses Shed during 1 Year by an Immunocompromised Child., Clin Infect Dis. 2006 Dec 15;43(12):1555-1561. 2006.<o:p></o:p>


What about a non toxic molecule, produced by a low cost & easily transferable technique?
http://www.leaddiscovery.co.uk/admin%20technology/files/14429.asp
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Given that the writers are from Univ of Michigan, isn't that where Y. Kawaoka works? I wonder if he's tested this on H5N1?

How far down the test-test-test-approval track is it?

.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Florida1 said:
I understand this. There is some inconsistent data. There is a sequence mystery. There are missing sequences. Yes, we want them.

There are many dedicated individuals that work at the International agencies and Federal departments.

I am not going to argue about this. Publicly berating these groups does not result in release.
Click to expand...


Depending on the jurisdiction governing the lab/government department in question, a formal application under the freedom of information laws may yield results, or at least cryptic reasons for the refused access. The process is often lengthy, fraught with minute exceptions, negotiation and appeals. However, public information is presumed accessible in most examples of freedom of information legislation, and the fact of the formal application itself sometimes embarasses entities into providing the information, especially if the application is made from a news agency or legal counsel.

I must agree with F1, however. Open and public hostility against the administrators in charge of the information concurrent with a formal access application will just slow problem-solving down to a bureaucratic snail's pace. Better to come to the process with "clean hands", be patiently quiet during the process, and reserve any well-founded criticisms until the end.

Obtaining legal counsel in the jurisdiction who is knowledgeable with access legislation would be very prudent.

J.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

http://www.upi.com/InternationalIntelligence/view.php?StoryID=20070119-050750-6910r

U.N.: Bird flu drug effective

UNITED NATIONS, Jan. 19 (UPI) -- The U.N. health agency will not withdraw its recommendation of oseltamivir, the drug used to fight bird flu, despite new information about its effectiveness.

The announcement, made Friday by the U.N. World Health Organization, comes following news from Egypt of two cases of genetic mutation in people that moderately reduced oseltamivir's effectiveness.

The Geneva-based WHO says the level of resistance to the drug is not yet well established and the virus has not become more easily transmittable between humans.

"At this time there is no indication that oseltamivir resistance is widespread in Egypt or elsewhere," the agency said in its latest update.

WHO also said this mutation in the H5N1 virus had first been identified in 2005 in a single case in Vietnam. Current laboratory testing suggested the resistance was only moderate.

"Based on these considerations, the public health implications at this time are limited," the agency said.

The first human case of H5N1 was reported in January 2004, and was linked to widespread outbreaks affecting birds in Vietnam and Thailand. U.N. health officials have warned the virus could evolve into a human pandemic if it mutates into a form that could transmit easily between people.

The two cases found in Egypt, involving a 16-year-old girl and her 26 year-old uncle, both ended in death. Both patients had been on treatment with oseltamivir for two days before the clinical samples were taken.

.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

AlaskaDenise said:
Given that the writers are from Univ of Michigan, isn't that where Y. Kawaoka works? I wonder if he's tested this on H5N1?

How far down the test-test-test-approval track is it?

.
Click to expand...

It is as effective as the classic antiviral rimantadine (in dose,effectiveness)

It work on H5N1 as it does on others sub-type.

mechanism...we know that it stick to the hemaglutinnine.

We also know that it's propriety make this peptide integrate our mammalian cells membrane & provide it effect there.

It is called Entry Blocker.

The peptide may provide a prophylactic effect there for a time. This time we call the half-life of the molecule.

This half-life is shorter than with an organic chemistry molecule such as oseltamivir but the toxicity is almost absent because it is an easily metabolisable molecule made of naturals amino acids linked in the same way as the they are in every life form on earth.

Some simples peptide design rules tricks can drastically change the spread at wich it is metabolized by the body.
One of theses "rules" is known since almost ten year now.
The "N-terminal rule"

It can also be linked to others biological protean where it can be protected from the degradation metabolism until it reach the target cells.

The linking mechanisms to an organic chemistry molecule are patented however.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

...are patented however.
Click to expand...

by whom?

Is the production process currently available.?

What about capacity and material availability?

.
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Guess...

Chemie.DE News-Center: Roche and Schering-Plough resolve peginterferon patent disputes [34K]
Aug 2006
...the European peginterferon patent of Roche currently pending in the European Patent Office will be withdrawn...each other under all their patents applicable to their pegylated...agreement are not disclosed. Pegylation is the process that attaches...
more hits from [http://www.chemie.de/news/e/4293/?ps=&pw=a&t=&defop=an...]
similar results
Click to expand...
Chemie.DE News-Center: Roche and Schering-Plough resolve peginterferon patent disputes [34K]
Aug 2006
...the European peginterferon patent of Roche currently pending in the European Patent Office will be withdrawn...each other under all their patents applicable to their pegylated...agreement are not disclosed. Pegylation is the process that attaches...
more hits from [http://www.chemie.de/news/e/4293/?ps=&pw=a&t=&defop=an...]
Click to expand...
Insulin inhalation--Pfizer/Nektar Therapeutics: HMR 4006, inhaled PEG-insulin--Nektar, PEGylated insulin--Nektar.
Drugs in R&D, Jan 2004
...Therapeutics is using its Advanced PEGylation technology to develop a dry...repeating units of ethylene oxide. PEGylation is designed to increase the...Therapeutics was granted US patent 5,997,848 on a method for delivering inhalable insulin. The patent covers a method for delivering...
Click to expand...
But in fact many companys have deposed patent in this, maybe they can depose a patent for every specific molecule to wich the link the PEG molecule...?
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

The EB based on the fibroblast growth factor 4 (FGF-4) signal sequence is could be a good candidate for structure based drug design and replace or complete the current therapeutic options. It is specific, has significant dose dependent broadspectrum antiviral activity against influenza viruses at low micromolar concentrations and low cytotoxicity, providing 100% protection against numerous subtypes including the highly pathogenic H5N1 viruses in vivo and in vitro, but it is not as effective in postinfection treatment. Studies are under way to determine if a modified peptide of shorter length is as effective or more effective<?xml:namespace prefix = o ns = "urn:schemas-microsoft-com:office:office" /><o:p></o:p>
<o:p></o:p>
The EB peptide acts also on other virus types such as HSV but has no effect on HIV. The main effect in influenza viruses is the inhibition of viral attachment, probably through interaction with the HA protein the viral entry is affected only in high concentrations. The mecanism of inhibition is still unclear.<o:p></o:p>
<o:p></o:p>
Peptides have been widely described in the inhibition of bacterial infections and viral infections <o:p></o:p>
<o:p></o:p>
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Multivalent lectins as inhibitors of viral fusion and entry in
cells: new antiviral mechanism ​

Pr Leonid V. Chernomordik Section on Membrane Biology, Laboratory of Cellular and Molecular Biophysics, National Institute of Child Health and Human Development, National Institutes of health, Bethesda, Maryland, USA ​

Natural antiviral defenses mediated by the innate immune systems involve defensins, antimicrobial peptides expressed by leukocytes and by epithelial cells. We explored an antiviral activity of a theta-defensin retrocyclin-2, RC2 1. We found RC2 to inhibit influenza virus infection by blocking viral entry into host cells at a stage of fusion between viral envelope and cell membrane. Binding of RC2, a multivalent lectin, to cell and viral surface carbohydrates prevented fusion by erecting a network of crosslinked and immobilized surface glycoproteins. RC2 also inhibited fusion mediated by Sindbis virus and baculovirus. Two other multivalent lectins in innate immunity, human beta defensin-3 and mannan-binding lectin, blocked viral fusion by the same mechanism ?​

source: Asian European Conference on Avian Influenza 2006
June 29 - 30 2006​
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

Egyptian Ministry of Health press release from the day the 'Tamiflu resistance' story came out...

Google-translated from Arabic:

The Ministry of Health is conducting tests developed for all samples of avian influenza virus, January 18, 2007

The Ministry of Health and Population in collaboration with the World Health Organization and the Joint Research Navy (Namro 3) and the Center for Disease Control in Atlanta (CDC) of the United States, conducting advanced tests of all samples of avian influenza virus which had been isolated cases of human infection, which took place in Egypt in order to determine the genetic map and a knowledge of developments that may occur in and the consequent occurrence.

Yani, in the framework of the Ministry's efforts to follow up the developments, which could arise on the epidemiological situation of the avian influenza virus and the belief regional and global role in the fight against this disease.

On that basis, the study shows that genetic viruses isolated from patients who died of avian influenza last month that there had been breakthroughs can be associated with H5N1 drug resistance Altamiflo.

Because of this development should be considered scientifically accurate communication has been the World Health Organization to study the significance of the presence of these mutations, dimensions and impact on the global and national efforts to combat avian influenza disease has been reached to the following points:

1-We need more time to analyze this matter and study the various facts concerning him.

2-Is H5N1 for the continuous jumps since he appeared until now, this is not the first time that had happened in the developments of the virus has been observed similar leap in virus isolated from human patients previously avian influenza in Vietnam.

3-This surge has led to the emergence of a breed of virus could cause a global epidemic so far and there is no evidence of an increased ability to move the virus among humans Therefore, the World Health Organization still considers the situation in the level of preparedness (3), which is the same the world situation since 2003.

4-Had failed to prove that the property has lost Altamiflo totally ineffective, and there are still other drugs effective against these viruses are available leap and the Ministry of Health and Population.

The Ministry of Health and Population contacts with all international organizations and bodies to modernize the global plan to combat the disease in accordance with the developments and to provide the best possible service to the citizens of Egypt.

The World Health Organization expressed admiration for transparency and cooperation of the Ministry of Health and Population in Egypt.

http://birdflu.sis.gov.eg/ahtml/aflu0540.htm
 
Re: New Strain of Bird Flu Found in Egypt Is Resistant to Antiviral Drug

It's encouraging to see so many scientists working together on this issue & prompt release of sequences. I hope this situation can serve as a model.

Thanks to each and every contributor for their prompt attention to this issue and willingness to put aside publication rights & other personal issues in the battle against this monster. :applause:

.
 
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